Cancer is the second leading cause of death in the United States, exceeded only by heart disease. (Cancer Facts and Figures 2004, American Cancer Society, Inc.). Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for new drugs effective in monotherapy or in combination with existing agents as first line therapy, and as second and third line therapies in treatment of resistant tumors.
Cancer cells are by definition heterogeneous. For example, within a single tissue or cell type, multiple mutational “mechanisms” may lead to the development of cancer. As such, heterogeneity frequently exists between cancer cells taken from tumors of the same tissue and same type that have originated in different individuals. Frequently observed mutational “mechanisms” associated with some cancers may differ between one tissue type and another (e.g., frequently observed mutational “mechanisms” leading to colon cancer may differ from frequently observed “mechanisms” leading to leukemias). It is therefore often difficult to predict whether a particular cancer will respond to a particular chemotherapeutic agent (Cancer Medicine, 5th edition, Bast et al., B. C. Decker Inc., Hamilton, Ontario).
Components of cellular signal transduction pathways that regulate the growth and differentiation of normal cells can, when dysregulated, lead to the development of cellular proliferative disorders and cancer. Mutations in cellular signaling proteins may cause such proteins to become expressed or activated at inappropriate levels or at inappropriate times during the cell cycle, which in turn may lead to uncontrolled cellular growth or changes in cell-cell attachment properties. For example, dysregulation of receptor tyrosine kinases by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand has been implicated in the development and progression of human cancers.
RET (rearranged during transfection) receptor is a novel oncogene that encodes the RET receptor tyrosine kinase. RET has essential roles in cell survival, differentiation, proliferation and migration. Studies have shown that RET binds to, and tyrosine phosphorylates, beta-catenin and that the interaction between RET and beta-catenin can be direct and independent of cytoplasmic kinases, such as SRC. Data have also shown that the beta-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human carcinomas. Oncogenic activation of RET has been shown to cause the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in various thyroid carcinomas
Tec is a member of the non-receptor, cytoplasmic protein-kinase Tec family, where amino acid sequence is highly conserved among members. Tec has a pleckstrin homology (PH) domain, a Tec homology (TH) domain, a Src homology (SH)-2 domain, an SH-3 domain and a kinase domain. The PH domain binds to membrane phospholipids, and SH-2 and SH-3 domains mediate protein-protein interactions. Tec family kinases play key roles in receptor signaling required for cell activation, differentiation and development.
Alterations in the activity (expression) of the Tec gene are associated with various disorders, diseases and other deleterious conditions. The altered gene expression may lead to diseases, disorders and conditions include inflammatory, proliferative, hyperproliferative and immunologically-mediated diseases. Diseases and conditions associated with Tec family tyrosine kinases also include cancers, for example, leukemia and lymphomas, two major cancers occurring in children in the United States.
Eph receptors and their ligands, the ephrins, represent a large class of cell-cell communication molecules with well-defined developmental functions. Eph/Ephrin genes are widely expressed in all adult organs with certain organ-site-specific patterns. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated. More recent studies have shown that EphA8 is down-regulated in some cancer and proliferative disorders, such as, colon cancer and glioblastomas.
The ephrin type-A receptor 8 (EphA8) gene encodes a member of the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. The protein encoded by this gene functions as a receptor for ephrin A2, A3 and A5 and plays a role in short-range contact-mediated axonal guidance during development of the mammalian nervous system.
Accordingly, new compounds and methods for modulating RET, EphA8 and Tec genes and treating proliferation disorders, including cancer, are needed. The present invention addresses these needs.